Strategies to treat cancer have focused primarily on the killing of tumor cells. Here, we describe a differential stress resistance (DSR) method that focuses instead on protecting the organism but not cancer cells against chemotherapy. Short-term starved S. cerevisiae or cells lacking proto-oncogene homologs were up to 1,000 times better protected against oxidative stress or chemotherapy drugs than cells expressing the oncogene homolog Ras2val19. Low-glucose or low-serum media also protected primary glial cells but not six different rat and human glioma and neuroblastoma cancer cell lines against hydrogen peroxide or the chemotherapy drug/pro-oxidant cyclophosphamide. Finally, short-term starvation provided complete protection to mice but not to injected neuroblastoma cells against a high dose of the chemotherapy drug/pro-oxidant etoposide. These studies describe a starvation-based DSR strategy to enhance the efficacy of chemotherapy and suggest that specific agents among those that promote oxidative stress and DNA damage have the potential to maximize the differential toxicity to normal and cancer cells.

https://www.pnas.org/content/pnas/105/24/8215.full.pdf

Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy

Radiation is used in the treatment of a broad range of malignancies. Exposure of normal tissue to radiation may result in both acute and chronic toxicities that can result in an inability to deliver the intended therapy, a range of symptoms, and a decrease in quality of life. Radioprotectors are compounds that are designed to reduce the damage in normal tissues caused by radiation. These compounds are often antioxidants and must be present before or at the time of radiation for effectiveness. Other agents, termed mitigators, may be used to minimize toxicity even after radiation has been delivered. Herein, we review agents in clinical use or in development as radioprotectors and mitigators of radiation-induced normal tissue injury. Few agents are approved for clinical use, but many new compounds show promising results in preclinical testing.

Radioprotectors and Mitigators of Radiation-Induced Normal Tissue Injury

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among patients with diabetes mellitus (DM). DM can lead to multiple cardiovascular complications, including coronary artery disease (CAD), cardiac hypertrophy, and heart failure (HF). HF represents one of the most common causes of death in patients with DM and results from DM-induced CAD and diabetic cardiomyopathy. Oxidative stress is closely associated with the pathogenesis of DM and results from overproduction of reactive oxygen species (ROS). ROS overproduction is associated with hyperglycemia and metabolic disorders, such as impaired antioxidant function in conjunction with impaired antioxidant activity. Long-term exposure to oxidative stress in DM induces chronic inflammation and fibrosis in a range of tissues, leading to formation and progression of disease states in these tissues. Indeed, markers for oxidative stress are overexpressed in patients with DM, suggesting that increased ROS may be primarily responsible for the development of diabetic complications. Therefore, an understanding of the pathophysiological mechanisms mediated by oxidative stress is crucial to the prevention and treatment of diabetes-induced CVD. The current review focuses on the relationship between diabetes-induced CVD and oxidative stress, while highlighting the latest insights into this relationship from findings on diabetic heart and vascular disease.

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Diabetic Cardiovascular Disease Induced by Oxidative Stress

Oxidative & nitrosative stress in depression: why so much stress?

Neurobiological basis of chemotherapy-induced cognitive impairment: a review of rodent research.

The present study investigated the prophylactic influence of melatonin against cyclophosphamide-induced oxidative stress in mouse tissues. Lipid peroxidation, reduced glutathione (GSH), glutathione disulphide (GSSG), glutathione peroxidase (GSH-Px) and serum phosphatase levels were analyzed in brain, spleen liver, lungs, kidney and testes. Fifteen days oral administration with melatonin (0.1 mg/kg bw per day) before treatment checked the augmentation of the level of lipid peroxidation, blood GSSG and acid phosphatase caused by an acute treatment with a radiomimetic drug, cyclophosphamide (75 mg/kg bw). Cyclophosphamide-induced depletion in the level of GSH, GSH-Px and alkaline phosphatase was made up statistically significant by chronic melatonin administration given orally. The results indicate the antioxidative properties of melatonin resulting into its prophylactic property against the cyclophosphamide-induced biochemical alterations. The finding support the idea that melatonin is a potent free-radical scavenger and antioxidant.

Prophylactic action of melatonin against cyclophosphamide-induced oxidative stress in mice.

The present study is a pilot study that explores the antioxidative properties of linseed (Linum usitatissimum) oil in its prophylactic action against oxidative stress induced by a radiomimetic drug, cyclophosphamide. Oral administration of linseed oil (0.1 mL/kg of body weight/day) for 20 days prior to an acute dose of cyclophosphamide (75 mg/kg) significantly inhibited the augmented level of malondialdehyde, conjugated dienes, and hydroperoxides in the mouse brain. The cyclophosphamide- induced decline in the levels of reduced glutathione, glutathione peroxidase, and alkaline phosphatase was also significantly prevented by linseed oil in mouse blood. Similarly, the increased activity of acid phosphatase and oxidized glutathione was significantly inhibited by linseed oil. Results clearly indicate the prophylactic action of linseed oil against cyclophosphamide- induced oxidative stress.

Prophylactic Action of Linseed (Linum usitatissimum) Oil Against Cyclophosphamide-Induced Oxidative Stress in Mouse Brain

Study on pre-treatment of melatonin against radiation-induced oxidative stress in mice

Flaxseed (linseed, Linum usitatissimum, Linaceae) is widely used for its edible oil in many parts of the world. The present study investigates the radioprotective and antioxidative potential of flaxseed oil (FO). Swiss albino mice were administered FO orally once daily for 15 consecutive days, then exposed to a single dose of 5 Gy of gamma radiation. Lipid peroxide, reduced glutathione and total protein were estimated in the liver. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), acid and alkaline phosphatase estimations in serum were also carried out. Radiation-induced increases in the levels of lipid peroxidation (LPO), AST, ALT and acid phosphatase were significantly ameliorated by flaxseed oil pretreatment, and radiation-induced depletion in the level of glutathione (GSH) and alkaline phosphatase activities was significantly inhibited by flaxseed oil administration. The lifespan was increased in the flaxseed oil treated irradiated mice in comparison with their respective control mice, with survival data showing an LD50/30 (lethal dose for 50% of animals after 30 days) of 7.1 and 10 Gy for control and FO treated irradiated mice, respectively, and produced a dose reduction factor for flaxseed oil (DRF) of 1.40. Radiation-induced deficits in body and organ weight were significantly reduced or prevented in flaxseed oil pretreated mice. The protection afforded by flaxseed oil may be attributed to the constituents of the oil, which include omega-3 essential fatty acids and phytoestrogenic lignans, which appear to play an important role in free radical scavenging and singlet oxygen quenching. The study does not rule out the possibility of a prophylactic potential of flaxseed oil against radiation-induced degenerative changes in liver. Copyright © 2007 John Wiley & Sons, Ltd.

Prophylactic effect of flaxseed oil against radiation-induced hepatotoxicity in mice.

The ever-increasing understanding of oxygen radical-linked diseases, including the biological process of aging, has stimulated general interest in modulating these biological events Melatonin has been reported to have antioxidant properties in addition to its known hormonal activities However, reports on low-level chronic administration with its anti-aging influence are scanty Hence, the present study was aimed to investigate the influence of low-dose chronic administration (010 mg/kg body weight/day for 3 months) of melatonin against age-induced oxidative stress in mice tissues, namely brain, liver, spleen and kidney Sixteen-month-old mice were supplemented with melatonin (010 mg/kg body weight/day) for three months and then autopsied (at the age of 19 months) for the biochemical estimation of lipid peroxidation, reduced glutathione (GSH), glutathione disulphide (GSSG), glutathione peroxidase (GSH-Px) and serum phosphatase activity Results indicate that age-induced augmentation (compared to 6-8-week-old mice) in the level of lipid peroxidation, GSSG and acid phosphatase is significantly (P < 0001) ameliorated in melatonin-treated mice Age-induced decline in the level of GSH, GSH-Px and alkaline phosphatase activity is inhibited significantly by the long-term administration of melatonin The findings indicate that low-dose chronic administration of melatonin acts as a free radical scavenger and anti-aging agent

A.L. Bhatia

Papers

Prophylactic action of melatonin against cyclophosphamide-induced oxidative stress in mice.

Prophylactic Action of Linseed (Linum usitatissimum) Oil Against Cyclophosphamide-Induced Oxidative Stress in Mouse Brain

Study on pre-treatment of melatonin against radiation-induced oxidative stress in mice

Prophylactic effect of flaxseed oil against radiation-induced hepatotoxicity in mice.

Melatonin-induced reduction in age-related accumulation of oxidative damage in mice.